Acquired immune deficiency syndrome (AIDS) is a disease of retroviral etiology, characterized by immune dysfunction, opportunistic infections, and eventually death. Murine acquired immune deficiency syndrome (MAIDS), induced by infection with the murine LP-BM5 leukemia retrovirus (MuLV) mixture, causes a progressive and profound immunodeficiency. It is strikingly similar to human AIDS, with splenomegaly, lymphadenopathy, and hypergammaglobulinemia in the early stage of retrovirus infection, progressive defects in T and B cell function, and reduction of host resistance to pathogens and neoplasia. These similarities exist even though human immunodeficiency virus (HIV), a lentivirus, and the retrovirus causing murine AIDS, MuLV, a C-type retrovirus, represent different types of retroviruses (1).
The immunopathogenic mechanisms underlying HI V infection and disease are not unidimensional; they are extremely complex (2). Preferential expansion, deletion, and activation of some CD4.sup.+ .alpha..beta. T cells induced by retroviral super or chronic antigen (Ag) exposure in human and murine AIDS may be important immunopathogenic mechanisms (3-5). Selective Ag activation of CD4.sup.+ .alpha..beta. T cells may lead to polyclonal stimulation of T and B cells at early stages, with subsequent aberrant cytokine production CD4.sup.+ T cell depletion. Eventually, these abnormalities lead to profound immunosuppression of cell-mediated immunity and immunodeficiency (2).
The aberrant cytokine production due to retrovirus infection, caused by a switch from T helper 1 (Th1) response to T helper 2 (Th2) response, promotes the progression to AIDS (6). In HIV.sup.+ /AIDS patients and MuLV-infected mice, T cell proliferation and Th1 cytokine (interleukin-2 (IL-2) and interferon-.gamma.) production decline, while Th2 cytokine (IL-4, IL-5, IL-6, and IL-10), and Ig production increase (7-10). The Th1 to Th2 conversion may determine the fatal outcome of the disease as part of the mechanism producing severe immunodeficiency and loss of disease resistance during the progression to AIDS. When IL-4-deficient mice (IL-4 gene knockout) that are defective in Th2 cytokine responses are infected with LP-BM5 retrovirus, there is no lethality, and the development of T cell abnormalities associated with murine retrovirus infection is delayed (11). Administration of anti-IL-4 monoclonal antibody (Mab) to LP-BM5 retrovirus-infected mice or restoring the Th1 cytokine, IFN, by injection also normalizes the imbalance of Th1 and Th2 responses induced by retrovirus infection, prevents retrovirus-induced suppression of immune responses, and alleviates the typical murine AIDS symptoms: splenomegaly and hypergammaglobulinemia (12).
Autoantibodies (AAb) binding a peptide determinant corresponding to the first complementarity determining region (CDR1) of the T-cell receptor (TCR) V.beta. domain were elevated early in murine retrovirus infection (13). Elevation of the levels of these AAbs is an early event following retroviral infection that corresponds in part to the general polyclonal activation of B cells with selectivity for particular V.beta. sequences that occurs later. The production of high levels of anti-TCR AAb early in this disease with continued production of some AAbs suggests that they might be involved in retrovirus immunopathogenesis. The AAb directed against CDR1 determinants can be considered natural Ab against public or regulatory idiotypes (Id) (14), since this region is the least variable of the CDR and is completely specified by the V.beta. gene sequence.
Preferential expansion of some TCR .alpha..beta. CD4.sup.+ T cells induced by retroviral superantigens in both human and murine retrovirus infection is an important immunopathogenic mechanism (2, 5). Selective expansion/deletion of some TCR .alpha..beta. CD4.sup.+ T cells may lead to polyclonal activation of T and B cells at an early stage, and subsequent aberrant cytokine production. Eventually these abnormalities lead to profound immunodeficiency with immunosuppression of cell-mediated immunity.